Introduction: Monoclonal gammopathy of undetermined significance (MGUS) results from clonal proliferation of differentiated plasma cells producing homogeneous immunoglobulin or its light (or, rarely, heavy) chain, and is associated with an increased risk of multiple myeloma (MM), Waldenström macroglobulinemia, or other malignant lymphoproliferative disorders.  Programmed cell death protein 1 and its ligand 1 (PD-1, PD-L1) are major inhibitory receptors regulating T cell exhaustion, i.e. a state of T cell dysfunction. The role of lymphocyte activation and exhaustion in the natural history of MGUS is still a matter of discussion. Aim of the study was to determine the percentages and numbers of exhausted and activated lymphocytes B and T in peripheral blood and bone marrow of MGUS patients. Moreover, we analyzed relationship between the number of PD-1-positive and PD-L1-positive lymphocytes and established prognostic factors in MGUS. Material and methods: The study included 30 untreated patients with MGUS and 20 healthy subjects. The immunophenotype of peripheral blood mononuclear cells and bone marrow cells was determined by means of flow cytometry. Results: Patients with MGUS showed higher frequencies and absolute number of exhausted B lymphocytes CD19+PD-1+ (p<0.001), CD19+PD-L1+ (p<0.001), activated lymphocytes B with phenotypes CD19+CD25+ (p<0.001) and CD19+CD69+ (p<0.001), as well as higher frequencies and absolute number of exhausted T lymphocytes CD3+PD-1+ (p=0.032), CD3+PD-L1+ (p=0.041), and activated CD3+CD25+ (p=0.033), and CD3+CD69+ (p=0.016) lymphocytes T than the controls in the peripheral blood. Similar observations were done in the bone marrow samples (p<0.001, p<0.001, p<0.001, p<0.001, p=0.012, p=0.019, p=0.044, and p=0.023, respectively). Enhanced exhaustion and activation of lymphocytes were associated with increased concentration of monoclonal protein and beta-2 microglobulin, and progression of the disease. Conclusions: The study confirmed the association between unfavorable prognosis and high expression of exhaustion and activation markers in MGUS patients. Determination of PD-1+, PD-L1+, CD25+ and CD69+ lymphocytes constitutes valuable diagnostic tool.